Process for the catalytic enantioselective reduction of ketones

ABSTRACT

The invention involves a procedure for the catalytic enantioselective reduction of ketones to chiral alcohols. Heretofore, this reaction was carried out batch-wise. Because, in this procedure, one utilizes a catalyst increased in size with polymer, it is possible to carry out the reaction in a quasi-continuous manner in a membrane reactor. In contrast to the state of the art, one thus dramatically increases the operative life of the catalyst.

This is the national phase of PCT/EP97/06479, filed Nov. 20, 1997, nowWO 98/22415.

FIELD OF THE INVENTION

The invention involves a procedure for the catalytic enantioselectivereduction of ketones to chiral alcohols.

DISCUSSION OF THE PRIOR ART

Chiral alcohols are, for example, important intermediates in thepharmaceutical industry. There is therefore a great interest inprocedures which make these compounds available in high optical purity.In conjunction therewith, catalytic procedures are particularlyadvantageous since with the use of small quantities of the generallyexpensive chiral auxiliaries, a multiple of the chiral product can beproduced.

A procedure of this type is, for example, the oxazaborolidine-catalyzedreduction of ketones to chiral alcohols with boranes, for example,borane dimethylsulfide complex, or borane tetrahydrofuran complex (seefor example, Wallbaum, S. and Martens, J., in Tetrahedron Asymmetry 31992, 1475-1504). The reaction is set forth in FIG. 1. This methodprovides chiral alcohols in good to very good yield and enantiomericexcess (enantiomeric excess=ee). In this manner a series ofpharmaceutically relevant compounds can be produced.

In general, for the achievement of an optimal enantiomeric excess,between about 5 to 10 mol/% of the catalyst (relative to the ketone) isneeded. A minimization of the catalyst expenses can therefore make acrucial contribution to the cost advantage of the procedure.

Many attempts have been undertaken to raise the cycling number (mols ofproduct per mol of spent catalyst). Thus for example, theoxazaborolidines utilized as catalysts were immobilized on insolublecarriers. These heterogeneous oxazaborolidines were obtained by couplingthe utilized chiral amino alcohol ligands to a cross-linked polystyreneresin with boric acid groups (Franot, et al., in Tetrahedron Asymmetry6, 1995, 2755-2766). The thus obtained heterogeneous catalyst can befiltered off after the reaction and charged anew. Already duringcarrying out of the third reaction cycle, the enantiomeric excessachieved, drops under 80% so that further provision of the catalyst isno longer meaningful. Therefore by this means, the cyclic number canonly be negligibly raised from 10 (corresponding to 10 mol % catalyst)up to 20 to 30.

SUMMARY OF THE INVENTION

The purpose of the present invention was to solve the technical problemof making a procedure available which enables the effective exploitationof the chiral catalyst.

This problem is solved by the present invention in that the catalyticenantioselective reduction of ketones to chiral alcohols with amolecular weight increased catalyst is carried out in a membranereactor. By means of this procedure in accordance with the presentinvention, one is surprisingly able to raise the cycling number by afactor of 10 to 120 moreover without loss of the enantioselectivity ofthe charged catalyst. Moreover, this procedure delivers the chiralalcohols in enantiomeric excess of 90% ee. The retention, as well as theseparation of the soluble catalyst by the membrane such as for example,an ultra or nanofiltration membrane, has furthermore the advantage thatthe reaction can be carried out in a homogeneous solution withoutmaterial transportation limitations.

As catalyst, the charging of a chiral oxazaborolidine is particularlyadvantageous. As catalysts however, there may also be utilizedtransition metal compounds such as for example titanates, which then,via the chiral ligands, for example diol-ligands, can be coupled to thecompound utilized for molecular weight increase.

The preferred oxazaborolidine of the present invention has two possiblepositions for molecular weight enlargement. A coupling of this substanceto the compound utilized in molecular weight increase can occur eithervia an amino alcohol or a boron acid. Preferably the oxazaborolidine inaccordance with the present invention, is coupled to the molecularweight increasing compound via the chiral amino alcohol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram of the prior art.

FIG. 2 illustrates certain preferred ligands.

FIG. 3 is a schematic flow diagram of the process of the presentinvention.

FIG. 4 is a plot of turnover and enantioselective excess against reactorrun time.

DISCUSSION OF THE PREFERRED EMBODIMENTS

As ligands, in principle all the chiral amino alcohols may be utilizedwhich have a) (further) functional group which enables the binding, inparticular however, tyrosinol or hydroxy proline derivatives aredesirable. Specifically, diphenyl tyrosinol and diphenyl hydroxyprolinol(FIG. 2) achieve very good results.

For molecular weight enlargement, there is suitably utilized a polymer,in particular a polystyrene or polysiloxane, a molecular weightenlargement of the catalyst as well as its precursors can also beachieved by the coupling of the appropriate compounds, for example, todendrimers. The coupling occurs in that a ligand is coupled to a readypoly or dendrimer via a functional group not required for catalysis.Alternatively, the ligand can also be provided with a polymerizablefunctionality which can become copolymerized with another monomer.

The substances taking part in the catalytic enantioselective reductionof the present invention should preferably be homogeneously soluble inorganic solvents.

The active oxazaborolidine catalyst is formed from the chiral aminoalcohols in the presence of (utilized for reduction) borane (BH₃) underthe splitting off of two equivalents of hydrogen. This can either takeplace in situ in the reactor or separately before the catalyst is washedinto the reactor.

Also, the reaction of the amino alcohol ligands with different boronacids or boron acid derivatives can be utilized for the formation ofoxazaborolidines. The molecular weight increased catalysts are thencharged to a suitable membrane reactor for the continuously drivenenantioselective reduction of prochiral ketones.

The flow diagram of such a reactor construction is set forth in FIG. 3.The two educts, the borane as well as the ketone, are dissolved in asuitable organic solvent, in particular toluene or tetrahydrofluran(THF) pumped via a pump into the membrane reactor from reservecontainers standing under a protective gas to the exclusion of oxygenand air humidity. This comprises for example a stirring cell with asolvent stable ultra or nanofiltration membrane (flat membrane). It isalso possible to utilize hollow fiber modules. At the reactor exit, thereaction mixture (via a T-piece) is quenched with methanol in order toliberate the produced chiral alcohol and perhaps destroy any surplusborane.

Such a reactor can be run in a stable manner for several days, that isto say, over long contact times. An exemplary reaction run is set forthin FIG. 4. Very high turnovers and enantiomer excesses are achieved inaccordance with the procedures of the present invention. Thus, a veryhigh space—time yield is achieved, which is an important criterion forthe economic viability of the process.

In comparison to the utilization of free—or also heterogeneous catalystsin a batch reactor, a large part of the preparation time is avoided bythe use of the continual process mode. In comparison to the situationwith a similar batch reactor, the large amounts of borane containingreaction solution and the dangers connected therewith are avoided.

The work-up of the product solution in comparison to production in abatch reactor, is substantially simplified since the catalyst need nolonger be separated out. The removal of surplus borane proceeds in asimple manner. It can either be distilled off as a boric acid trimethylester subsequent to methanol quenching, or it is readily available afteraqueous work-up as boric acid in alkaline extraction. Through the highturnovers, that is to say, through approximately quantitative conversionof the ketone into the alcohol and avoidance of appearance ofby-products, the purification of the accrued product is simplified ifnot actually superfluous.

By utilization of the process of the present invention, a plurality ofketones can be economically converted into the chiral alcohols. Throughthe use of molecular weight increased homogeneous solutions ofoxazaborolidines, the cycling number of these catalysts can besubstantially increased without, as with other procedures, acceptance ofa reduction of the enantioselectivity. Rather, surprisingly in part,even better enantioselectivity is noticed compared to free catalysts ina batch reactor. Hereinbelow, the invention will be further explained bymeans of examples.

EXAMPLES Example I Formation of Polymer Increased α,α-Diphenyltyrosinol

To a solution of 86° mmol phenyl magnesium bromide, produced from 22 gmagnesium and 90 ml bromobenzene in 900 ml tetrahydrofuran (THF), 21 gof tyrosine ethylester hydrochloride (85 mmol) were added batch-wise at0° C. and stirred at room temperature overnight. Subsequently,hydrolysis with ammonium chloride solution is carried out. The organicphase is separated and the aqueous phase extracted four (4) times withethyl acetate. The combined organic phases are dried over sodium sulfateand the solvent distilled off. Double recrystallization from ethanolgives 17 g of (S)-2-amino-3-(4-hydroxyphenyl)-1,1-diphenyl propan-1-ol(=α,α-diphenyl tyrosinol, 62% yield). This is reacted in dimethylformamide with 1 equivalent of sodium hydride and after cessation of H₂generation (circa 1 hour) is reacted with an equimolecular amount ofvinyl benzyl chloride. After stirring for 5 hours at room temperature,the reaction mixture is poured into an excess of water and the whiteprecipitate filtered off and recrystallized from ethanol to yield(S)-2-amino-3-(4-(vinyl phenylmethoxy)-1,1-diphenylpropan-l-ol inapproximately 45% yield.

13 g of this monomer (29.9 mmol) are copolymerized with 5 equivalents offreshly distilled styrene (150 mmol) under the utilization of 275 mg ofazobisisobutyronitrile as radical initiator in 220 ml of toluene. Themixture is stirred for 50 hours at 60° C. under argon. The polymer isthen precipitated in methanol to yield 15.1 g of polymer, correspondingto a 53% yield. The mean molecular weight as determined by gelpermeation chromatography is 13,800.

Example II A Continuous Reduction in a Membrane Reactor

The reactor arrangement for the continuous enantioselective reductioncorresponds to the scheme set forth in FIG. 3. As reserve containers,there are utilized conventional 3-necked flasks which are placed underprotective gas. Teflon hoses are utilized as conduits. As pumps, thereare utilized Pharmacia P-500 Reciprocating Piston Pumps. The membranereactor comprises a polypropylene flat membrane cell with 10 ml reactionvolume, stirred with a magnetic stirrer. It is equipped with asolvent-stable nanofiltration membrane MPF 50 (manufactured by MembraneProducts).

The pump and the reactor are rinsed with absolute (water-free) THF.Subsequently, 0.5 mmol of the polymer bound ligands corresponding to 50mol % catalyst (dissolved in THF) are pumped into the membrane reactorvia one of the pumps. The reactor is now rinsed for 1-2 hours with asolution of borane dimethyl sulfide (BH₃—SMe₂) in THF (200 mmol/L, 10-20ml/hr). Thereby there is formed the oxazaborolidine from the aminoalcohol held back in the membrane reactor.

Then a solution of 200 mmol/L of acetophenone in THF is dosed into thereactor via the second pump. The flows of both pumps are set to 5 ml/hr.The contact time T=1 hour, and the initial concentration of ketone andborane are each 100 mmol/L. Via T-piece at the reactor exit, quenchingtakes place with 4 ml/hr. of methanol. The reaction product is collectedin a fraction collector. Turnover and ee are measured gaschromatographically. A corresponding reactor sequence is reproduced inFIG. 4. It shows that the reactor can be stabilely run for a substantiallength of time and turnovers of up to 100% can be obtained. Thus theprocess of the present invention delivers the sought enantiomeric excessof equal to or greater than 90% ee.

What is claimed is:
 1. A process for the catalytic enantioselectivereduction of ketones to chiral alcohols, wherein the reaction is carriedout in a membrane reactor comprising an organic solvent stable ultra ornanofiltration membrane utilizing a catalytic agent soluble in anorganic solvent comprising a chiral catalyst coupled to a polymer or adendrimer.
 2. The process in accordance with claim 1, wherein the chiralcatalyst is a chiral oxazaborolidine.
 3. The process in accordance withclaim 1, wherein the oxazaborolidine is coupled to a polymer via achiral amino alcohol moiety attached to said polymer.
 4. The processaccording to claim 3, wherein the chiral amino alcohol moiety isdiphenyl tyrosinol or diphenyl hydxroxy proline.
 5. The process inaccordance with claim 1 wherein the chiral catalyst is coupled to apolymer.
 6. The process in accordance with claim 5, wherein the polymeris a polystyrene or a polysiloxane.
 7. The process in accordance withclaim 1 wherein the chiral catalyst is coupled to a dendrimer.